International Journal for Parasitology: Drugs and Drug Resistance最新文献

{"title":"Culturing of Giardia lamblia under microaerobic conditions can impact metronidazole susceptibility by inducing increased expression of antioxidant enzymes","authors":"Kateryna Starynets ,&nbsp;Ana Paunkov ,&nbsp;Anja Wagner ,&nbsp;Klaus Kratochwill ,&nbsp;Christian Klotz ,&nbsp;David Leitsch","doi":"10.1016/j.ijpddr.2025.100585","DOIUrl":"10.1016/j.ijpddr.2025.100585","url":null,"abstract":"<div><div>The microaerophilic/anaerobic protist <em>Giardia lamblia</em> is a world-wide occurring parasite of the human small intestine. It causes giardiasis which manifests as diarrhoea accompanied by other sequelae. Giardiasis is most commonly treated with either the 5-nitroimidazole metronidazole or the benzimidazole albendazole. Unfortunately, the number of refractory cases is increasing, which is probably caused, at least in part, by drug resistance. However, most attempts to isolate metronidazole-resistant <em>G</em>. <em>lamblia</em> strains from patients have failed so far because the parasites were not resistant when tested <em>in vitro</em>.</div><div>We hypothesized that this failure might be caused by drug assay conditions which are standardly anaerobic, and performed metronidazole susceptibility testing with two well studied strains, i.e. WB C6 and BRIS/87/HEPU/713 (strain 713) under microaerophilic conditions. Indeed, 713 proved to be less susceptible to metronidazole under microaerophilic conditions as compared to anaerobic conditions, and residual growth was even noted at concentrations of metronidazole similar to those in the serum of treated patients (i.e. about 100 μM). Further experiments showed that 713 also grows much faster under microaerobic conditions than WB C6. Reduced susceptibility to metronidazole under microaerobic conditions was also observed in a clinical isolate from a refractory giardiasis case.</div><div>Two-dimensional gel electrophoresis showed that microaerobic growth was accompanied by the upregulation of superoxide reductase, a pyridoxamine 5′-phosphate oxidase putative domain-containing protein, and a TlpA-like protein in 713 but not in WB C6. All three proteins are known, or can be predicted to have antioxidant functions. Indeed, overexpression of pyridoxamine 5′-phosphate oxidase in WB C6 from a plasmid carrying the respective gene behind the arginine deiminase promoter significantly improved growth of the transfected cell line under microaerobic conditions. Moreover, similarly overexpressed superoxide reductase conferred significant protection against metronidazole.</div><div>Our results suggest that oxygen concentrations can affect the outcomes of metronidazole treatment against <em>G</em>. <em>lamblia</em>.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100585"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143179624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of risk factors associated with Ancylostoma spp. infection and the benzimidazole F167Y resistance marker polymorphism in dogs from the United States","authors":"Pablo D. Jimenez Castro ,&nbsp;Jennifer L. Willcox ,&nbsp;Haresh Rochani ,&nbsp;Holly L. Richmond ,&nbsp;Heather E. Martinez ,&nbsp;Cecilia E. Lozoya ,&nbsp;Christian Savard ,&nbsp;Christian M. Leutenegger","doi":"10.1016/j.ijpddr.2025.100584","DOIUrl":"10.1016/j.ijpddr.2025.100584","url":null,"abstract":"<div><div><em>Ancylostoma caninum</em> is the most significant intestinal nematode parasite of dogs. We acquired fecal surveillance data from a large population of dogs in the United States (US). A diagnostic test using real-time PCR (qPCR) for <em>Ancylostoma</em> spp. and allele-specific qPCR detecting the SNP F167Y in the isotype 1 of the Beta-tubulin gene, was used in 885,424 randomized canine fecal samples collected between March 2022 and December 2023. Overall, <em>Ancylostoma</em> spp. had a prevalence of 1.76% (15,537/885,424), with the highest in the South 3.73% (10,747/287,576), and the lowest in the West 0.45% (632/140,282). Within the subset of <em>Ancylostoma</em> spp<em>.-</em>detected dogs used for further analysis, the F167Y SNP had an overall prevalence of 14.44% with the highest in the West and the lowest in the Midwest (10.76%). The greyhound exhibited a higher prevalence of <em>Ancylostoma</em> spp. infections (17.03%) and a higher prevalence of the F167Y polymorphism (33.6%) compared to non-greyhounds (13.7% and 2.08%), respectively, but were not associated with the highest risk for the F167Y polymorphism. Sex did not influence hookworm infection nor F167Y polymorphism prevalence. Intact dogs had a prevalence of hookworm infection and F167Y polymorphism of 3.88% and 15.66%, respectively. Puppies showed increased prevalence of hookworms (3.70%) and the F167Y SNP (17.1%). Greyhounds, bluetick coonhounds, and boerboels had the highest relative risks for hookworm infection, while Cavalier King Charles spaniels, Havanese, and shiba inus had the lowest. The top and bottom three with the highest and lowest RR for the F167Y SNP were the old English sheepdog, American foxhound, and toy poodle Toy, and shih tzu, Maltese, and Australian cattle dogs, respectively. This study highlights the value of an accessible diagnostic qPCR test with fast turnaround in unraveling the molecular epidemiology of hookworms and benzimidazole resistance, as well as explore potentially important risk factorsin dogs with routine veterinary care.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100584"},"PeriodicalIF":4.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143222955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining the zebrafish embryo developmental toxicity assay (ZEDTA) with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant women","authors":"Lucia Borrallo-Lopez ,&nbsp;Laura Guzman ,&nbsp;Noelia G. Romero ,&nbsp;Anna Sampietro ,&nbsp;Ana Mallo-Abreu ,&nbsp;Laia Guardia-Escote ,&nbsp;Elisabet Teixidó ,&nbsp;Burkhard Flick ,&nbsp;Xavier Fernàndez-Busquets ,&nbsp;Diego Muñoz-Torrero ,&nbsp;Marta Barenys","doi":"10.1016/j.ijpddr.2025.100582","DOIUrl":"10.1016/j.ijpddr.2025.100582","url":null,"abstract":"<div><h3>Background</h3><div>Malaria during pregnancy implies a high risk for the mother and the developing child. However, the therapeutic options for pregnant women have historically been very limited, especially during the first trimester of pregnancy due to potential adverse effects on embryo-fetal development. Recently, there has been great controversy regarding these potential embryo-fetal adverse effects because the results of rodent studies were not in accordance with the clinical data available, and finally the WHO has changed the recommendations for pregnant women with uncomplicated <em>P. falciparum</em> malaria to treatment with artemether-lumefantrine during the first trimester. The discrepancy between pre-clinical and clinical studies has been attributed to species-differences in the duration of the window of susceptibility of circulating primitive erythroblasts.</div></div><div><h3>Methods</h3><div>Here we provide a tool based on an alternative method to animal experimentation that accelerates the research of novel drugs for pregnant women. We have adapted the zebrafish embryo developmental toxicity assay to include hemoglobin staining in the embryos and two time-points of lethality and dysmorphogenesis evaluation. These two time-points were selected to include one when the development is independent of and one when the development is dependent of erythrocytes function. The method was used to test four marketed antimalarial drugs and three new antimalarial drug candidates.</div></div><div><h3>Results</h3><div>Our combination of tests can correctly predict the teratogenic and non-teratogenic effects of several antimalarial marketed drugs (artemisinin, quinine, chloroquine, and dihydroartemisinin + desbutyl-lumefantrine). Furthermore, we have tested three new drug candidates (GS-GUAN, DONE3TCl, and YAT2150) with novel mechanisms of action, and different from those of the marketed antimalarial drugs.</div></div><div><h3>Conclusions</h3><div>We propose a decision tree combining the results of the two time-points of evaluation together with the information on significant erythrocyte depletion. The aim of this decision tree is to identify compounds with no or lower hazard on teratogenicity or erythrocyte depletion at an early phase of the drug development process.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100582"},"PeriodicalIF":4.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective activity of Tabebuia avellanedae against Giardia duodenalis infecting organoid-derived human gastrointestinal epithelia","authors":"Giulia Rigamonti ,&nbsp;Fabrizia Veronesi ,&nbsp;Elisabetta Chiaradia ,&nbsp;Petra Gosten-Heinrich ,&nbsp;Antonia Müller ,&nbsp;Leonardo Brustenga ,&nbsp;Stefano de Angelis ,&nbsp;Alessia Tognoloni ,&nbsp;Riccardo De Santo ,&nbsp;Christian Klotz ,&nbsp;Marco Lalle","doi":"10.1016/j.ijpddr.2025.100583","DOIUrl":"10.1016/j.ijpddr.2025.100583","url":null,"abstract":"<div><div><em>Giardia duodenalis</em> is a widespread intestinal protozoan that affects mammals, including humans. Symptoms can range from being subclinical to causing severe abdominal pain and diarrhoea. Giardiasis often requires repeated treatment with synthetic drugs like metronidazole. In recent years, treatment failures in clinical cases involving nitroimidazoles have been increasingly reported. Consequently, identifying therapeutic alternatives is necessary. Medicinal plants have traditionally been used as antiparasitic compounds, but systematic evaluation under controlled experimental conditions is often lacking. Here, we evaluated the <em>in vitro</em> efficacy of <em>Tabebuia avellanedae</em> dry and hydroalcoholic extracts, as well as one of its active compounds, β-lapachone, as potential treatment against <em>G. duodenalis</em> infection. We observed effective antigiardial activity for all tested compounds, with β-lapachone exhibiting lower IC₅₀ values than metronidazole. Cytotoxic effects often limit therapeutic concentration windows of opportunity, and choosing an informative model to assess them is not straightforward. In the present case, only <em>T. avellanedae</em> hydroalcoholic extract showed no cytotoxicity on tumoral human intestinal Caco-2 cell line, and only a trend of inhibition when tested on canine epithelial kidney MDCK cells. To introduce a more physiological test system, we used <em>in vitro G. duodenalis</em> infection experiments in a trans-well set-up using organoid derived monolayers (ODM) to assess at the same time drug efficacy against the parasite and safety on primary human intestinal epithelia, a likely surrogate for <em>in vivo</em> conditions. Our studies using this model point towards the potential therapeutic opportunity for non-systemic applications of <em>T. avellanedae</em> extracts and a relevant ingredient of these, β-lapachone. The data suggest that ODM co-cultures with <em>G. duodenalis</em> are suitable for testing antigiardial compounds, providing a more informative <em>in vitro</em> model before progressing to <em>in vivo</em> tests.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100583"},"PeriodicalIF":4.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the threonine metabolism of Echinococcus multilocularis: The threonine dehydrogenase as a potential drug target in alveolar echinococcosis","authors":"Marc Kaethner ,&nbsp;Pascal Zumstein ,&nbsp;Joachim Müller ,&nbsp;Matías Preza ,&nbsp;Philipp Grossenbacher ,&nbsp;Anissa Bartetzko ,&nbsp;Laura Vetter ,&nbsp;Martin Lochner ,&nbsp;Stefan Schürch ,&nbsp;Clement Regnault ,&nbsp;Daniel Villalobos Ramírez ,&nbsp;Britta Lundström-Stadelmann","doi":"10.1016/j.ijpddr.2025.100581","DOIUrl":"10.1016/j.ijpddr.2025.100581","url":null,"abstract":"<div><div>Alveolar echinococcosis (AE) is a severe zoonotic disease caused by the metacestode stage of the fox tapeworm <em>Echinococcus multilocularis</em>. We recently showed that <em>E. multilocularis</em> metacestode vesicles scavenge large amounts of L-threonine from the culture medium. This motivated us to study the effect of L-threonine on the parasite and how it is metabolized. We established a novel metacestode vesicle growth assay with an automated readout, which showed that L-threonine treatment led to significantly increased parasite growth. In addition, L-threonine increased the formation of novel metacestode vesicles from primary parasite cell cultures in contrast to the non-proteinogenic threonine analog 3-hydroxynorvaline. Tracing of [U-¹³C]-L-threonine and metabolites in metacestode vesicles and culture medium resulted in the detection of [U-¹³C]-labeling in aminoacetone and glycine, indicating that L-threonine was metabolized by threonine dehydrogenase (TDH). EmTDH-mediated threonine metabolism in the <em>E. multilocularis</em> metacestode stage was further confirmed by quantitative real-time PCR, which demonstrated high expression of <em>emtdh</em> in <em>in vitro</em> cultured metacestode vesicles and also in metacestode samples obtained from infected animals. EmTDH was enzymatically active in metacestode vesicle extracts. The compounds disulfiram, myricetin, quercetin, sanguinarine, and seven quinazoline carboxamides were evaluated for their ability to inhibit recombinantly expressed EmTDH. The most potent inhibitors, albeit not very strong or highly specific, were disulfiram, myricetin and sanguinarine. These compounds were subsequently tested for activity against <em>E. multilocularis</em> metacestode vesicles and primary parasite cells and only sanguinarine demonstrated significant <em>in vitro</em> activity. However, TDH is not its only cellular target, and it is also known to be highly toxic. Our findings suggest that additional targets of sanguinarine should be explored, and that it may serve as a foundation for developing more specific compounds against the parasite. Moreover, the EmTDH assay could be a valuable high-throughput, target-based platform for discovering novel anti-echinococcal compounds.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100581"},"PeriodicalIF":4.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3′-deoxytubercidin: A potent therapeutic candidate for the treatment of Surra and Dourine","authors":"Kayhan Ilbeigi ,&nbsp;Dorien Mabille ,&nbsp;Rajdeep Roy ,&nbsp;Mirco Bundschuh ,&nbsp;Ewout Van de Velde ,&nbsp;Fabian Hulpia ,&nbsp;Serge Van Calenbergh ,&nbsp;Guy Caljon","doi":"10.1016/j.ijpddr.2025.100580","DOIUrl":"10.1016/j.ijpddr.2025.100580","url":null,"abstract":"<div><div>Surra and Dourine are widespread diseases caused by two protozoan parasites <em>Trypanosoma brucei evansi</em> and <em>Trypanosoma brucei equiperdum</em>, respectively. A wide range of animals including camels, horses, cattle and buffaloes are susceptible to infection. These diseases pose a significant socio-economic burden, primarily due to the limited therapeutic options and the complications associated with toxicity and drug resistance, making disease management particularly challenging. This study evaluated the potential of 3′-deoxytubercidin, a previously identified antitrypanosomal nucleoside, as a therapeutic candidate for Surra and Dourine using mouse models. Mice infected with either <em>T. b. evansi</em> or <em>T. b. equiperdum</em> were treated with 3′-deoxytubercidin at a dosage of 6.25 mg kg⁻¹ administrated intraperitoneally once daily for five consecutive days. The treatment resulted in full cure, as confirmed by both microscopic examination and quantitative PCR, without any observed toxicity. Given the importance of considering the One Health concept in developing new antiparasitic drugs for veterinary use, the environmental impact of 3′-deoxytubercidin was assessed through the ecotoxicity tests on aquatic organisms, conducted in accordance with OECD guidelines. The compound showed some toxicity to <em>Daphnia</em> (EC₅₀ = 0.54 mg L⁻¹ in acute <em>Daphnia</em> test) but had no significant adverse effects on green alga at concentrations tested (up to 50 mg L⁻¹). This study confirms the suitability of 3′-deoxytubercidin as an effective and safe therapeutic candidate for further development in the treatment of Surra and Dourine, highlighting its potential for improving disease management in affected regions.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100580"},"PeriodicalIF":4.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biotransformation of anthelmintics in nematodes in relation to drug resistance","authors":"Ondřej Vosála ,&nbsp;Josef Krátký ,&nbsp;Petra Matoušková ,&nbsp;Nikola Rychlá ,&nbsp;Karolína Štěrbová ,&nbsp;Lucie Raisová Stuchlíková ,&nbsp;Ivan Vokřál ,&nbsp;Lenka Skálová","doi":"10.1016/j.ijpddr.2025.100579","DOIUrl":"10.1016/j.ijpddr.2025.100579","url":null,"abstract":"<div><div>In all organisms, the biotransformation of xenobiotics to less toxic and more hydrophilic compounds represents an effective defense strategy. In pathogens, the biotransformation of drugs (used for their elimination from the host) may provide undesirable protective effects that could potentially compromise the drug's efficacy. Accordingly, increased drug deactivation via accelerated biotransformation is now considered as one of the mechanisms of drug resistance. The present study summarizes the current knowledge regarding the biotransformation of anthelmintics, specifically drugs used to treat mainly nematodes, a group of parasites that are a significant health concern for humans and animals. The main biotransformation enzymes are introduced and their roles in anthelmintics metabolism in nematodes are discussed with a particular focus on their potential participation in drug resistance. Similarly, the inducibility of biotransformation enzymes with sublethal doses of anthelmintics is presented in view of its potential contribution to drug resistance development. In the conclusion, the main tasks awaiting scientists in this area are outlined.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100579"},"PeriodicalIF":4.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitroxoline evidence amoebicidal activity against Acanthamoeba castellanii through DNA damage and the stress response pathways","authors":"Lijun Chen ,&nbsp;Wei Han ,&nbsp;Wenwen Jing ,&nbsp;Meng Feng ,&nbsp;Qingtong Zhou ,&nbsp;Xunjia Cheng","doi":"10.1016/j.ijpddr.2025.100578","DOIUrl":"10.1016/j.ijpddr.2025.100578","url":null,"abstract":"<div><div><em>Acanthamoeba castellanii</em> is a widespread unicellular eukaryote found in diverse environments, including tap water, soil, and swimming pools. It is responsible for severe infections, such as <em>Acanthamoeba</em> keratitis and granulomatous amebic encephalitis, particularly in individuals with immunocompromisation. The ability of protozoans to form dormant and persistent cysts complicates treatment, as current therapies are ineffective against cyst stages and suffer from poor specificity and side effects. Nitroxoline, a quinoline derivative with well-established antibacterial, antifungal, and antiviral properties, is a promising therapeutic candidate. This study aimed to elucidate cellular signalling events that counteract the effects of nitroxoline. In this study, nitroxoline significantly reduced the viability of <em>A</em>. <em>castellanii</em> trophozoites in a dose- and time-dependent manner, inducing morphological changes and apoptosis. Transcriptomic analysis revealed substantial alterations in gene expression, including enrichment of metabolic pathways, DNA damage responses, and iron ion binding. Nitroxoline treatment upregulated genes involved in DNA repair and oxidative stress response while regulating genes in the methionine and cysteine cycles. It also decreased the mitochondrial membrane potential, H₂S production, and total iron amount in <em>A</em>. <em>castellanii</em>. Bioinformatic analyses and molecular docking studies suggest direct interactions between nitroxoline and several <em>A</em>. <em>castellanii</em> proteins. Our research provides a comprehensive molecular map of the response of <em>A</em>. <em>castellanii</em> to nitroxoline, revealing significant changes in gene expression related to the stress response and metabolic pathways. These findings underscore the potential of nitroxoline as a potent anti-<em>Acanthamoeba</em> agent, offering new insights into its mechanism of action and paving the way for effective combinational therapeutic strategies.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100578"},"PeriodicalIF":4.1,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modified dosing schedule efficacy of fosmidomycin and clindamycin against murine malaria Plasmodium berghei","authors":"Leah A. Walker,&nbsp;Vision Bagonza,&nbsp;Bryce Bobb,&nbsp;David J. Sullivan","doi":"10.1016/j.ijpddr.2024.100577","DOIUrl":"10.1016/j.ijpddr.2024.100577","url":null,"abstract":"<div><div>Fosmidomycin and clindamycin target the <em>Plasmodium</em> apicoplast. Combination clinical trials have produced mixed results with the primary problem being the recrudescent infection frequency by day 28. Given that antibiotic efficacy against bacterial infections often depends on the constant drug presence over several days, we hypothesized that the antimalarial blood or liver stage efficacy of fosmidomycin and clindamycin could be improved by implementing a more frequent dosing schedule. A blood stage murine malaria <em>P. berghei</em> GFP-luciferase low and high parasitemia model was implemented to follow pharmacodynamics and cure for modified dose, schedule and duration of individual and combination fosmidomycin and clindamycin. <em>P. berghei</em> sporozoites were used to investigate fosmidomycin during the 48 h murine liver stage. Here we observed that the same total dose of fosmidomycin and clindamycin, alone and in combination, are more efficacious when scheduled in smaller, more frequent doses. Fosmidomycin added measurably small additional killing in combination with clindamycin. Despite dosing every 6 h during liver stages, fosmidomycin was inhibitory, but noncurative even with addition of atorvastatin to decrease hepatocyte production of mevalonate. We have also demonstrated <em>in vitro</em> efficacy of fosmidomycin and clindamycin against <em>P. falciparum</em> C580Y with IC₅₀s similar to those for drug sensitive <em>P. falciparum</em>. The dosing schedule of quinoline and artemisinin partner drugs fosmidomycin or clindamycin targeting the apicoplast should maximize time above minimum inhibitory concentration.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100577"},"PeriodicalIF":4.1,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative DNA metabarcoding reveals species composition of a macrocyclic lactone and pyrantel resistant cyathostomin population in the UK","authors":"K.E. Bull ,&nbsp;J. Hodgkinson ,&nbsp;K. Allen ,&nbsp;J. Poissant ,&nbsp;L.E. Peachey","doi":"10.1016/j.ijpddr.2024.100576","DOIUrl":"10.1016/j.ijpddr.2024.100576","url":null,"abstract":"<div><div>Cyathostomins are the most abundant equid endoparasites globally. There are approximately fifty cyathostomin species and, whilst they occupy distinct niches within the large intestine, they are generally considered to share similar characteristics in terms of pathogenicity and response to drug treatment. There are three classes of anthelmintic licensed in the UK to treat cyathostomins (benzimidazoles, tetrahydropyrimidines and macrocyclic lactones) and cases of resistance have been documented for all classes. Previously, faecal egg count reduction tests (FECRT) on four UK Thoroughbred studs revealed multidrug resistant cyathostomins on one stud (A), with evidence of resistance to the macrocyclic lactones (MLs) ivermectin (IVM) and moxidectin (MOX), and to pyrantel (PYR). The remaining three studs (B-D) lacked resistance to IVM and MOX but had a shortened egg reappearance period post treatment.</div><div>To determine whether specific species could be associated with the observed resistance and shortened egg reappearance period, strongyle eggs collected from between six and 15 individual horses per stud were copro-cultured to third larval stage (L3), before and after anthelmintic treatment, over a three-year timeframe (2021–2023). Quantitative DNA metabarcoding of the ITS-2 region was carried out on all samples.</div><div>On stud A, single but differing species were found to be responsible for ML and pyrantel resistance in yearlings, <em>Cyathostomum catinatum</em> and <em>Cylicocyclus nassatus,</em> respectively. On studs B-D, with shortened egg reappearance periods, species composition remained largely unchanged post treatment.</div><div>This study is the first to quantitatively profile cyathostomin species composition pre- and post-treatment in a multidrug resistant population in the UK, revealing that resistance in cyathostomins was species specific. This raises the question of whether these species may be responsible for ML and PYR resistance more widely and indicates that anthelmintic resistance in cyathostomins may not be a multi-species phenomenon.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100576"},"PeriodicalIF":4.1,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}